The use of biomarkers for the care of patients with heart failure (HF) has expanded significantly. The natriuretic peptides (NPs), including B-type natriuretic peptide (BNP) and its amino-terminal cleavage equivalent (NT-proBNP) are now widely used for diagnosis, prognosis, and management of affected patients (Yancy et al., 2013 ACCF/AHA Guideline for the Management of Heart Failure: A report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines, Circulation, 2013; 128:e240-319). Following BNP and NT-proBNP, a wide range of novel biomarkers are being examined, each with potential promise for additive evaluation of patients suffering from the complex pathophysiology of HF. In this regard, there has been considerable effort to better understand the mechanistic link(s) between concentrations of cardiac biomarkers and the underlying cardiovascular pathophysiological processes from which they are released.
The natriuretic peptides have been found to be associated with a wide array of abnormalities of cardiovascular structure and function, including both systolic and diastolic function of the left ventricle (LV) (Tschope et al., The role of NT-proBNP in the diagnostics of isolated diastolic dysfunction: Correlation with echocardiographic and invasive measurements, Eur Heart J. 2005; 26:2277-2284, Weiner et al., Improvement in structural and functional echocardiographic parameters during chronic heart failure therapy guided by natriuretic peptides: Mechanistic insights from the proBNP outpatient tailored chronic heart failure (protect) study, Eur J Heart Fail. 2013; 15:342-351, Yu et al., Diastolic dysfunction and natriuretic peptides in systolic heart failure. Higher ANP and BNP levels are associated with the restrictive filling pattern, Eur Heart J. 1996; 17:1694-1702). Relative to the latter, identifying and grading severity of abnormal diastolic function is complex, with several echocardiographic parameters assessed in this exercise (Nagueh et al., Recommendations for the evaluation of left ventricular diastolic function by echocardiography, J Am Soc Echocardiogr. 2009; 22:107-133). While the natriuretic peptides are elevated in HF due to diastolic dysfunction, they are entirely non-specific in this association (Daniels et al., Natriuretic peptides, J Am Coll Cardiol. 2007; 50:2357-2368) thus limiting their applicability. Therefore, biomarker(s) predominantly useful to assist in the diagnosis and grading of abnormal diastolic function would be exceptionally valuable in clinical practice.
The insulin-like growth factor axis has previously been found to be a predictor of outcomes in HF (Watanabe et al., Insulin-like growth factor axis (insulin-like growth factor-i/insulin-like growth factor-binding protein-3) as a prognostic predictor of heart failure: Association with adiponectin, Eur J Heart Fail. 2010; 12:1214-1222). Insulin-like growth factor-binding protein 7 (IGFBP7) in particular was identified recently as a potential novel HF marker through proteomic and informatic searches of animal models of cardiac hypertrophy and human tissues of heart failure (Chugh et al., Pilot study identifying myosin heavy chain 7, desmin, insulin-like growth factor 7, and annexin a2 as circulating biomarkers of human heart failure, Proteomics, 2013; 13:2324-2334). IGFBP7 was principally associated with cardiac hypertrophy and was expressed at high levels in HF, but not in normal serum. IGFBP7 also appears to be expressed in the vasculature, potentially regulating angiogenesis (van Breevoort et al., Proteomic screen identifies IGFBP7 as a novel component of endothelial cell-specific weibel-palade bodies, J Proteome Res. 2012; 11:2925-2936).
Myocardial diastolic dysfunction is a different type of heart failure versus myocardial systolic dysfunction. Heart failure (HF) patients need to be stratified separately and specifically for therapy of diastolic dysfunction. Several new drugs are in development for the treatment of diastolic dysfunction: LCZ696 (Novartis PhIII), Sildenafil, Spironolactone, Anakinra, HISDN.
Diagnosis of diastolic dysfunction is time and cost consuming. A functional and structural classification is needed with imaging means.
Growth-differentiation factor-15 (GDF-15) is a member of the transforming growth factor-β cytokine superfamily. GDF-15 has been described as a strong predictor of cardiovascular events and an indicator for cardiovascular complications (Brown, D. A. et al., 2002 The Lancet, 359: 2159-2163; US2003/0232385; Kempf 2006, Circ Res 98: 351-360). Kempf et al. showed that circulating levels of GDF-15 are related to severity of CHF and predict the risk of death in patients with chronic heart failure (Clinical Chemistry 53:2; 284-291 (2007); Am Coll Cardiol, 2007; 50:1054-1060).